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    • 专利摘要:

    公开号:ES2860981T9
    申请号:ES16709877T
    申请日:2016-02-25
    公开日:2021-12-30
    发明作者:Tara Fourre；Robert J Gambogi；Anthony R Geonnotti；Patricia L Golas；Benjamin Serbiak
    申请人:Johnson and Johnson Consumer Inc；
    IPC主号:
    专利说明:

    [0002] Compositions comprising combinations of organic acids
    [0004] FIELD OF THE INVENTION
    [0006] The present invention relates to compositions comprising combinations of organic acids as defined in the claims. Their uses are also described. The present invention relates to compositions comprising combinations of succinic acid and aconitic acid. Uses of such compositions to disrupt biofilms are also disclosed.
    [0008] BACKGROUND OF THE INVENTION
    [0010] Organic acids and combinations thereof have been identified for use in a wide variety of compositions, including oral care compositions. For example, International Publication No. WO2012/001347 describes oral health compositions comprising extracts of shiitake mushrooms, chicory, and/or raspberry, and low molar mass fractions derived from the extracts. These compositions as described may comprise, or may be supplemented, with one or more of the following compounds: quinic acid, adenosine, inosine, trans-aconitic acid, cis-aconitic acid, oxalic acid, adenosine, and succinic acid. Although the reference claims anti-biofilm effects of its compositions through various mechanisms of action, it does not disclose any unexpected benefits resulting from any particular combination of the above compounds.
    [0012] Lillian Chen et al., Food and Beverage Applications, AN 1068, 2013 presents the characterization of ionic composition profiles in fruit juices and wines and the determination of organic acids in selected juice and wine samples. WO2013/072932 describes oral care compositions and methods for maintaining oral health. JP2011105651 discloses a spray composition for an oral cavity which is said to continuously improve dry mouth. WO2015/099754 describes compositions for oral care.
    [0014] SUMMARY OF THE INVENTION
    [0016] Applicants have unexpectedly discovered that certain combinations of organic acids can be combined to make compositions that tend to show significant and unexpected benefits, including increased biofilm disruption.
    [0018] The present invention relates to compositions comprising succinic acid, aconitic acid, and a carrier, wherein the succinic acid and aconitic acid are present in a ratio of from about 0.9:1 to 14:1, and wherein the combined amount total succinic acid and aconitic acid is 0.1 to 2% w/w of the composition.
    [0020] Also disclosed are methods of disrupting a biofilm comprising applying to a surface having a biofilm a composition of the claimed invention.
    [0022] Also disclosed are methods of disrupting a biofilm from a surface comprising applying to a surface having a biofilm a composition of the claimed invention.
    [0024] Also described are methods of reducing bacterial attachment to a surface comprising applying a composition of the claimed invention to the surface.
    [0026] BRIEF DESCRIPTION OF THE DRAWINGS
    [0028] Figure 1 is a graph of percent biofilm removal after multiple treatments (vs. water) vs. percent reduction in bacterial attachment (vs. water) for formulations containing succinic acid (SA) and aconitic acid (AA). in variable proportions at a total concentration of 21 mM (0.25-0.37% w/w, depending on the ratio of SA to Aa, see table 7).
    [0029] Figure 2 is a graph of percent biofilm removal after multiple treatments (vs. water) vs. percent reduction in bacterial attachment (vs. water) for formulations containing succinic acid (SA) and aconitic acid (AA). in variable proportions (different from those in Figure 1) at a total concentration of 21 mM (0.25-0.37% w/w, depending on the ratio of SA to AA, see table 7).
    [0030] DETAILED DESCRIPTION OF THE INVENTION
    [0032] All percentages listed in this specification are percentage solids/active amounts by weight, unless specifically stated otherwise.
    [0033] As noted above, applicants have unexpectedly discovered that compositions comprising combinations of succinic acid and aconitic acid in a carrier tend to show significant benefits over other combinations of organic acids. In particular, in certain embodiments, Applicants have discovered that such compositions exhibit a significant increase in biofilm disruption. More specifically, as described in more detail herein below and shown in the Tables and Figures, Applicants have found that combinations of succinic acid and aconitic acid tend to show a significant increase in both (a) the percentage of biofilm removal as in (b) the percentage reduction of bacterial attachment over other combinations of organic acids. Applicants indicate that, as used herein, "disrupting a biofilm" refers to the removal of biofilm from a surface, the reduction of bacterial attachment to a surface, or both.
    [0035] Any suitable succinic acid can be used in the present invention. Succinic acid, also known by the IUPAC systematic name butanedioic acid, or the historical name spirit amber is a diprotic dicarboxylic acid with chemical formula C 4 H 6 O 4 and structural formula HOOC- (CH 2) 2 -COOH. The succinic acid used herein may be derived naturally or synthetically. In certain embodiments, succinic acid is synthetically derived. Commercially available sources of succinic acid include Acros Organics, Alfa Aesar, Fisher Chemical, Fluka, MP Biomedicals, Sigma Aldrich, Spectrum Chemicals, and TCI Fine Chemicals.
    [0037] Any suitable aconitic acid can be used in the present invention. Aconitic acid, also known by the IUPAC systematic name, prop-1-ene-1,2,3-tricarboxylic acid, or the historical names alkyl acid, equisetic acid, cytridinic acid, or pyrocitric acid, is an organic acid with the formula chemistry C 6 H 6 O 6 and the structural formula HO 2 CCH=C(CO 2 H)CH 2 CO 2 H, and having two isomers cis-aconitic acid and trans -aconitic acid. In certain embodiments, trans-aconitic acid is used. In other embodiments, cisaconitic acid is used. The aconitic acid used herein may be derived naturally or synthetically. In certain embodiments, aconitic acid is synthetically derived. Commercially available sources of aconitic acid include Alfa Aesar, Fluka, MP Biomedicals, Parchem Fine & Specialty Chemicals, Sigma Aldrich, Spectrum Chemicals, and TCI Fine Chemicals.
    [0039] Any suitable amount and ratio of succinic acid and aconitic acid may be used in the compositions of the present invention. As those skilled in the art will recognize, based on their respective pKa values, the succinic and aconitic acids used in the present invention will be in equilibrium with their respective salt forms at most pHs. Accordingly, all amounts and ratios of succinic and aconitic acid described and claimed herein refer to the total amount of said acid in both its acid and salt forms in a particular composition. For example, a composition comprising 0.2% w/w succinic acid has a total amount of combined solid/active succinic acid in its acid and salt forms of 0.2% w/w based on the total weight of the composition. composition. A composition comprising a combined total amount of 1% w/w of succinic acid and trans-aconitic acid comprises a combined solid/active amount of succinic acid in its acid and salt forms and trans-aconitic acid in its acid and salt forms. 1% w/w based on the total weight of the compositions.
    [0041] In certain embodiments, succinic acid and aconitic acid are present in the composition in a combined total amount that is effective to prevent and disrupt biofilm formation in the oral cavity and in which the composition is stable. The composition contains succinic acid and aconitic acid in a total combined amount of 0.1 to 2% by weight based on the total weight of the composition (% w/w). In certain embodiments, the combined total amount of succinic acid and aconitic acid is 0.1 to 1% w/w of the composition, or 0.1 to 0.9% w/w of the composition, or 0. 1 to 0.5% w/w of the composition, or 0.1 to 0.3% w/w of the composition. In certain embodiments, the composition comprises a total combined amount of succinic acid and aconitic acid of from about 0.13% to about 0.89% w/w of the composition, from about 0.13% to about 0. 52% w/w of the composition, or from about 0.13% to 0.3% w/w of the composition.
    [0043] The ratio of succinic acid to aconitic acid in the compositions of the present invention (succinic:aconitic) is from 0.9:1 to 14:1. Also disclosed are compositions in which the ratio of succinic acid to aconitic acid is from about 0.9:1 to about 40:1, or from about 0.9:1 to about 20:1. In certain embodiments of the invention, the ratio of succinic acid to aconitic acid is from about 0.9:1 to about 9:1, or from about 0.9:1 to about 6:1, or from about 0.9: 1 to about 4:1. Also disclosed are compositions in which the ratio of succinic acid to aconitic acid is from about 1.1:1 to about 20:1, or from about 2.5:1 to about 20:1, or from about 6:1 to about 20:1. In certain embodiments of the invention, the ratio of succinic acid to aconitic acid is from about 1.1:1 to 14:1, or from about 2.5:1 to 14:1, or from about 6:1 to 14: 1, or from about 1.1:1 to about 9:1, or from about 2.5:1 to about 9:1, or from about 6:1 to about 9:1. Compositions in which the ratio of succinic acid to aconitic acid is from about 1.3:1 to about 20:1 are also disclosed. In certain embodiments of the invention, the proportion of acid succinic to aconitic acid is from about 1.3:1 to about 13:1, or from about 1.3:1 to about 8.33:1, or from about 1.3:1 to about 6:1, or from about 2.5:1 to about 13:1, or about 2.5:1 to about 8.33:1, or about 2.5:1 to about 6:1, or about 6:1 to about 8.33:1, or from about 4:1 to about 5.5:1. The ratio of succinic acid to aconitic acid is from 0.9:1 to 14:1.
    [0044] Any of a wide variety of orally acceptable carriers can be used in the present compositions. The vehicle may be aqueous or non-aqueous. The aqueous vehicle is generally water, although water/alcohol mixtures can also be used. In certain embodiments, water is added to q.s. (Quantum Sufficit, Latin for "as much as necessary") to the composition.
    [0045] In certain embodiments, the aqueous phase comprises from about 60% to about 95%, or from about 75% to about 90%, by weight of the composition. In certain compositions, water is present in an amount of from about 60% to about 95%, or from about 75% to about 90%.
    [0046] Alternatively, the compositions of the present invention may be formulated as a dry powder, chewing gum, film, semi-solid, solid or liquid concentrate. In such embodiments, for example, water is added to q.s. as required in the case of liquid concentrates or powder formulations, or the water may be removed using standard evaporation procedures known in the art to produce a composition in dry powder form. Evaporated or freeze-dried forms are advantageous for storage and shipping.
    [0047] In some embodiments, alcohol can be added to the composition. Any of a variety of alcohols represented by the formula R 3 -OH, where R 3 is an alkyl group having 2 to 6 carbons, can be used in the present invention. Examples of suitable alcohols of the formula R 3 -OH include ethanol; n-propanol, isopropanol; butanols; pentanols; hexanols and combinations of two or more thereof and the like. In certain embodiments, the alcohol is, or comprises, ethanol.
    [0048] In some embodiments, the alcohol may be present in the composition in an amount of from about 10.0% v/v or more of the total composition, or from about 10.0% to about 35.0% v/v of the total composition, or from about 15.0% to about 30.0% v/v of the total composition and may be from about 20.0% to about 25.0% v/v of the total composition .
    [0049] In some embodiments, the compositions may comprise a reduced level of alcohol. The phrase "reduced level" of alcohol means an amount of an alcohol R 3 -OH of about 10% v/v or less, or about 5% v/v or less, or about 1.0% v/v or less, or about 0.1% v/v or less by volume of the total composition. In certain embodiments, the compositions of the present invention are free of alcohols R 3 -OH.
    [0050] The compositions of the present invention preferably have a pH of less than 7. In certain embodiments, the composition has a pH of from about 3 to less than 7, or from about 3.5 to less than 7, or from about 3.5 to about 6.5, or about 3.5 to about 5.5, or about 3.5 to about 5.
    [0051] As those skilled in the art will recognize, the pH of the composition can be adjusted or achieved by using a buffer in an amount effective to provide the composition with a pH of less than 7. The composition can optionally comprise at least one pH modifying agent among those Useful in the present invention include acidifying agents to lower the pH, basifying agents to raise the pH, and buffering agents to control the pH within a desired range. For example, one or more compounds selected from acidifying, basifying, and buffering agents may be included to provide a pH of from about 2 to about 7, or in various embodiments from about 3 to about 6, or from about 4 to about 5. Any pH may be used. orally acceptable pH modifying agent including, without limitation, carboxylic and sulfonic acids, acid salts (eg, monosodium citrate, disodium citrate, monosodium malate, etc.), alkali metal hydroxides such as sodium hydroxide, borates, silicates, imidazole and mixtures thereof. One or more pH-modifying agents are optionally present in a total amount effective to maintain the composition in an orally acceptable pH range. In certain embodiments, inorganic acids can be used as a buffer added to the composition.
    [0052] In certain embodiments, organic acids can be used as a buffer added to the composition. Organic acids suitable for use in the compositions of the present invention include, but are not limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid, and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenolsulfonic acid, and mixtures thereof, optionally, the organic acid is selected from the group consisting of benzoic acid, sorbic acid, citric acid, and mixtures thereof, or optionally, the organic acid is benzoic acid.
    [0054] Generally, the amount of acid buffer is between about 0.001% (or about 0.001% w/v) and about 5.0% (or about 5.0% w/v) of the composition. In a certain embodiment, the organic acid buffer is present in amounts from 0.001% (or about 0.001% w/v) to 1.0% w/v (or about 1.0% w/v) of the composition, or between about 0.100% (or about 0.100% w/v) and about 1.0% (or about 1.0% w/v) of the composition.
    [0056] The compositions of the present invention may further comprise any of a variety of optional ingredients, including but not limited to, oil components, active ingredients, additional surfactants, humectants, solvents, flavors, sweeteners, colorants, preservatives, pH adjusters, buffers pH, and the like.
    [0058] Any of a variety of oil components can be used in the present compositions. The oily component may comprise one or more oils, or other materials that are insoluble in water, or substantially insoluble in water, meaning that their solubility is less than about 1% by weight in water at 25°C or, optionally , less than about 0.1%. In certain embodiments, the oil component of the present invention comprises, consists essentially of, or consists of at least one essential oil, i.e., a concentrated natural or synthetic hydrophobic material (or a combination thereof) of plant origin, which generally contains volatile compounds, in at least one flavoring oil, or a combination of two or more of them. Examples of essential oils, suitable flavoring oils and their amounts are described below. In certain embodiments, the composition comprises a total amount of oil component of about 0.05% w/w or more, about 0.1% w/w or more, or about 0.2% w/w or more of the oil component. .
    [0060] In certain embodiments, the compositions of the present invention comprise essential oils. Essential oils are volatile aromatic oils that may be synthetic or may be derived from plants by distillation, expression, or extraction, and usually carry the odor or aroma of the plant from which they are derived. Useful essential oils can provide antiseptic activity. Some of these essential oils also act as flavoring agents. Useful essential oils include, but are not limited to, citra, thymol, menthol, methyl salicylate (oil of wintergreen), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol, citronella, a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineole, linalool, ethyl linalaol, safrole vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, clary sage oil, rosemary oil, cinnamon oil, capsicum oil, bay oil, cedar leaf oil, gerianol, verbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter almond, chlorothymol, cinnamic aldehyde, oil of citronella, clove oil, coal tar, eucalyptus oil, guaiacol, tropolone derivatives such as hinokitiol, lavender oil, mustard oil, phenol, phenyl alicylate, pine oil, pine needle oil, sassafras oil, lavender spike oil, storax e, thyme oil, tolu balsam, turpentine oil, clove oil, and combinations thereof.
    [0062] In certain embodiments, essential oils are selected from the group consisting of thymol ((CH 3 ) 2 CHC 6 H 3 (CH 3 )OH, also known as isopropyl-m-cresol), eucalyptol (C 10 H 18 O, also known as cineol), menthol (CH 3 C 6 H g (C 3 H z )OH), aka hexahydrothymol), methyl salicylate (C 6 H 4 OHCOOCH 3 , aka oil of wintergreen), isomers of each one of these compounds, and combinations of two or more thereof. In some embodiments, the compositions of the present invention contain thymol. In some embodiments, the compositions of the present invention contain menthol. In some embodiments, the composition contains all four of these essential oils.
    [0064] In certain embodiments, thymol is employed in amounts from about 0.0001% to about 0.6% w/v, or from about 0.005% to about 0.07% w/v of the composition. In certain embodiments, eucalyptol may be employed in amounts of from about 0.0001% to about 0.51 w/v, or from about 0.0085% to about 0.10% w/v of the composition. In certain embodiments, the menthol is employed in amounts of from about 0.0001% to about 0.25% w/v, or from about 0.0035% to about 0.05% w/v of the composition. In certain embodiments, methyl salicylate is employed in amounts from about 0.0001% to about 0.28% w/v, or from about 0.004% to about 0.07% w/v of the composition. In certain embodiments, the total amount of all of these essential oils present in the disclosed compositions may be from about 0.0004% to about 1.64% w/v, or from about 0.0165% to about 0. 49% w/v of the composition.
    [0066] In certain embodiments, fluoride-providing compounds may be present in the mouthwash compositions of this invention. These compounds may be slightly soluble in water or may be completely soluble in water and are characterized by their ability to release fluoride ions or fluoride-containing ions in water. Typical fluoride-providing compounds are inorganic fluoride salts such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, cupric fluoride, zinc fluoride, stannic fluoride, stannous fluoride, barium fluoride, sodium hexafluorosilicate, ammonium hexafluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, sodium mono- and difluorophosphate aluminum and fluorinated calcium and sodium pyrophosphate. Amine fluorides can also be used, such as N'-octadecyltrimethylenediamine-N,N,N'-tris(2-ethanol)-dihydrofluoride and 9-octadecenylamine-hydrofluoride). In certain embodiments, the fluoride-providing compound is generally present in an amount sufficient to release up to about 5%, or from about 0.001% to about 2%, or from about 0.005% to about 1.5% of fluoride by weight of the composition.
    [0068] In certain embodiments, sensitivity-reducing agents, such as potassium nitrate and oxalate salts, may be incorporated into the present invention in an amount of from about 0.1% to about 5.0% w/v of the composition. Other potassium-releasing compounds (eg KCI) are feasible. High concentrations of calcium phosphates may also provide some additional sensitivity relief. These agents are believed to act by forming an occlusive surface mineral deposit on the surface of the teeth or by providing potassium to the nerves within the teeth to depolarize the nerves. A more detailed discussion of suitable sensitivity reducing agents can be found in US 2006/0013778 to Hodosh and US Patent No. 6,416,745 to Markowitz et al.
    [0070] In certain embodiments, compounds with anticalculus benefits (eg, various carboxylates, polyaspartic acid, etc.) may be incorporated into the present invention. Anionic polymeric polycarboxylates are also useful as anticalculus agents. Such materials are well known in the art, being used in the form of their free acids or partially or preferably fully neutralized water-soluble alkali metal (eg potassium and preferably sodium) or ammonium salts. Copolymers of 1:4 to 4:1 by weight maleic acid or anhydride with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of from about 30,000 to about 1,000,000, are preferred. These copolymers are available, for example, as Gantrez 25 AN 139 (M.W.
    [0071] 500,000), AN 119 (M.W. 250,000) and preferably S-97 Pharmaceutical Grade (M.W. 70,000), from GAF Chemicals Corporation
    [0073] Additional anticalculus agents may be selected from the group consisting of polyphosphates (including pyrophosphates) and salts thereof, polyaminopropanesulfonic acid (AMPS) and salts thereof; polyolefin sulfonates and salts thereof; polyvinylphosphates and salts thereof; polyolefin phosphates and salts thereof; diphosphonates and salts thereof; phosphonoalkane carboxylic acid and salts thereof; polyphosphonates and salts thereof; polyvinylphosphonates and salts thereof; polyolefin phosphonates and salts thereof; polypeptides; and mixtures thereof; carboxy-substituted polymers; and mixtures thereof. In one embodiment, the salts are alkali metal or ammonium salts. Polyphosphates are generally used as their fully or partially neutralized water-soluble alkali metal salts such as potassium, sodium, ammonium salts and mixtures thereof. Inorganic polyphosphate salts include alkali metal (eg sodium) tripolyphosphate, tetrapolyphosphate, dialkyl metal diacid (eg disodium), trialkyl metal monoacid (eg trisodium), potassium hydrogen phosphate, sodium hydrogen phosphate and hexametaphosphate. of alkali metals (eg, sodium), and mixtures thereof. Polyphosphates larger than tetrapolyphosphate usually occur as amorphous glassy materials. In one embodiment, the polyphosphates are those manufactured by FMC Corporation, which are commercially known as Sodaphos (#6), Hexaphos (#13), and Glass H (# 21, sodium hexametaphosphate), and mixtures thereof. Pyrophosphate salts useful in the present invention include alkali metal pyrophosphates, di-, tri-, and monopotassium or sodium pyrophosphates, dialkali metal pyrophosphate salts, tetraalkali metal pyrophosphate salts, and mixtures thereof. In one embodiment, the pyrophosphate salt is selected from the group consisting of trisodium pyrophosphate, disodium dihydrogen pyrophosphate (Na 2 H 2 P 2 Ü 7 ), dipotassium pyrophosphate, tetrasodium pyrophosphate (Na 4 P 2 Ü 7 ), tetrapotassium pyrophosphate ( K 4 P 2 O 7 ) and mixtures thereof. Polyolefin sulfonates include those in which the olefin group contains 2 or more carbon atoms, and salts thereof. Polyolefin phosphonates include those in which the olefin group contains 2 or more carbon atoms. Polyvinylphosphonates include polyvinylphosphonic acid. Diphosphonates and salts thereof include azocycloalkane-2,2-diphosphonic acids and salts thereof, azocycloalkane-2,2-diphosphonic acid ions and salts thereof, azacyclohexane-2,2-diphosphonic acid, azacyclopentane- 2,2-diphosphonic acid, N-methyl-azacyclopentane-2,3-diphosphonic acid, EHDP (ethane-1-hydroxy-1,1-diphosphonic acid), AHP (azacycloheptane-2,2-diphosphonic acid), ethane- 1-amino-1,1-diphosphonate, dichloromethane-diphosphonate, etc. The phosphonoalkane carboxylic acid or its alkali metal salts include PPTA (phosphonopropane tricarboxylic acid), PBTA (phosphonobutane-1,2,4-tricarboxylic acid), each as alkali or acid metal salts. Polyolefin phosphates include those in which the olefin group contains 2 or more carbon atoms. Polypeptides include polyaspartic and polyglutamic acids.
    [0075] In certain embodiments, zinc salts such as zinc chloride, zinc acetate, or zinc citrate may be added as an astringent for an "antiseptic cleansing" feel, as a respiratory protection enhancer, or as an anticalculus agent in an amount of about 0. 0.0025% w/v to about 0.75% w/v of the composition.
    [0076] Any of a variety of additional surfactants may be used in the present invention. Suitable surfactants may include anionic, nonionic, cationic, amphoteric, zwitterionic surfactants, and combinations of two or more thereof. Examples of suitable surfactants are disclosed, for example, in US Patent No. 7,417,020 to Fevola, et al.
    [0078] In certain embodiments, the compositions of the present invention comprise a nonionic surfactant. Those skilled in the art will recognize that any of a variety of one or more non-ionic surfactants include, but are not limited to, compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in nature. Examples of suitable nonionic surfactants include, but are not limited to, alkyl polyglucosides; alkyl glucose amines, block copolymers such as copolymers of ethylene oxide and propylene oxide, eg poloxamers; commercially available ethoxylated hydrogenated castor oils, for example, under the tradename CRODURET (Croda Inc., Edison, NJ); alkyl polyethylene oxide, eg polysorbates and/or; fatty alcohol ethoxylates; polyethylene oxide condensates) of alkylphenols; products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylenediamine; ethylene oxide condensates of aliphatic alcohols; long chain tertiary amine oxides; long chain tertiary phosphine oxides; long chain dialkyl sulfoxides; and mixtures thereof.
    [0080] Exemplary nonionic surfactants are selected from the group known as poly(oxyethylene)-poly(oxypropylene) block copolymers. Such copolymers are commercially known as poloxamers and are produced in a wide variety of structures and molecular weights with varying ethylene oxide contents. These non-ionic poloxamers are non-toxic and are acceptable as direct food additives. They are stable and readily dispersible in aqueous systems and are compatible with a wide variety of formulations and other ingredients for oral preparations. These surfactants should have an HLB (hydrophilic-lipophilic balance) of between about 10 and about 30, and preferably between about 10 and about 25. By way of example, nonionic surfactants useful in this invention include the poloxamers identified as poloxamers 105, 108 , 124, 184, 185, 188, 215, 217, 234, 235, 237, 238, 284, 288, 333, 334, 335, 338, 407 and combinations of two or more thereof. In certain preferred embodiments, the composition comprises poloxamer 407.
    [0082] In certain embodiments, the compositions of the claimed invention comprise less than about 9% nonionic surfactant, less than 5% or less than 1.5%, or less than 1%, or less than 0.8, less than 0 0.5%, less than 0.4% or less than 0.3% non-ionic surfactants. In certain embodiments, the composition of the present invention is free of nonionic surfactants.
    [0084] In certain embodiments, the compositions of the present invention also contain at least one alkyl sulfate surfactant. In certain embodiments, surfactants Alkyl suitable include, but are not limited to alcohols length carbon chain even numbered C8 to C 18 sulfated, optionally C 10 to C 16 sulfated neutralized with a suitable basic salt such as sodium carbonate or sodium hydroxide and mixtures thereof such that the surfactant has an alkyl chain length of C8 to even number of C 18, C 10 to C optionally 16. In certain embodiments, the alkyl sulfate is selected from the group consisting of sodium lauryl sulfate, hexadecyl sulfate, and mixtures thereof. In certain embodiments, mixtures of commercially available alkyl sulfates are used. A typical percentage decomposition of alkyl sulfates by alkyl chain length in commercially available sodium lauryl sulfate (SLS) is as follows:
    [0086] Length Percentage
    [0087] Component Chain
    [0088] of Rent in SLS
    [0089] C 12> 60%
    [0090] C 14 20% -35%
    [0091] C 16 <10%
    [0092] C 10 <1%
    [0093] C 18 <1%
    [0095] In certain embodiments, the alkyl sulfate surfactant is present in the composition at from about 0.001% to about 6.0% w/v, or optionally from about 0.1% to about 0.5% w/v of the composition. composition.
    [0097] Another suitable surfactant is one selected from the group consisting of sarcosinate surfactants, isethionate surfactants, and taurate surfactants. Preferred for use herein are the alkali metal or ammonium salts of these surfactants, such as the sodium and potassium salts of the following: lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate, and oleoyl sarcosinate. Sarcosinate surfactant may be present in the compositions of the present invention from about 0.1% to about 2.5%, or from about 0.5% to about 2%, by weight of the total composition.
    [0098] Synthetic zwitterionic surfactants useful in the present invention include derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals may be straight or branched chain, and in which one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, for example, carboxy, sulfonate, sulfate, phosphate or phosphonate.
    [0100] Amphoteric surfactants useful in the present invention include, but are not limited to, aliphatic secondary and tertiary amine derivatives in which the aliphatic moiety may be straight or branched chain and in which one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, eg, carboxylate, sulfonate, sulfate, phosphate or phosphonate. Examples of suitable amphoteric surfactants include, but are not limited to alkylimino dipropionates, alkyl lamphoglycinates (mono or di), alkylamphoproprionates (mono or di), alkylamphoacetates (mono or di), N-alkyl [3-aminopropionic acids, alkyl polyamino carboxylates, phosphorylated imidazolines, alkyl betaines, alkylamido betaines, alkylamidopropyl betaines, alkyl sultaines, alkylamido sultaines, and mixtures thereof. In certain embodiments, the amphoteric surfactant is selected from the group consisting of alkylamidopropyl betaines, amphoacetates such as sodium auroamphoacetate, and mixtures thereof. Mixtures of any of the above mentioned surfactants can also be used. A more detailed discussion of anionic, nonionic, and amphoteric surfactants can be found in US Patent No. 7,087,650 to Lennon; US Patent No. 7,084,104 to Martin et al.; US Patent No. 5,190,747 to Sekiguchi et al.; and US Patent No. 4,051,234 to Gieske, et al.
    [0102] In certain embodiments, compositions of the claimed invention comprise less than about 9% amphoteric surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8, less than 0.5% , less than 0.4%, or less than 0.3% amphoteric surfactants. In certain embodiments, the composition of the present invention is free of amphoteric surfactants.
    [0104] Additional surfactants may be added with the alkyl sulfate surfactant to aid in the solubilization of the essential oils as long as such surfactants do not affect the bioavailability of the essential oils. Suitable examples include anionic surfactants, nonionic surfactants, additional amphoteric surfactants, and mixtures thereof. However, in certain embodiments, the total surfactant concentration (including the alkyl sulfate surfactant alone or in combination with other surfactants) for the mouthrinses of the present invention should not exceed or exceed about 9% or less, optionally, the total concentration of surfactant should be about 5% or less, optionally about 1% or less, optionally about 0.5% or less of the % w/w active surfactant by weight of the composition.
    [0106] In certain embodiments, a sugar alcohol (humectant) is also added to the oral compositions of the present invention. The sugar alcohol solvent(s) may be selected from those multi-hydroxy-functional compounds which are conventionally used in oral and ingestible products. In certain embodiments, the sugar alcohols must be non-fermentable, non-metabolized sugar alcohols. In specific embodiments, sugar alcohols include, but are not limited to, sorbitol, glycerol, xylitol, mannitol, maltitol, inositol, allitol, altritol, dulcitol, galactitol, glucitol, hexitol, iditol, pentitol, ribitol, erythritol, and mixtures of the same. Optionally, the sugar alcohol is selected from the group consisting of sorbitol and xylitol or mixtures thereof. In some embodiments, the sugar alcohol is sorbitol. In certain embodiments, the total amount of sugar alcohol(s) added to effectively aid in the dispersion or dissolution of the mouthwash or other ingredients should not exceed about 50% w/w of the total composition. Or, the total amount of sugar alcohol should not exceed about 30% w/v of the total composition. Or, the total amount of sugar alcohol must not exceed 25% w/v of the total composition. The sugar alcohol may be in an amount of from about 1.0% to about 24% w/v, or from about 1.5% to about 22% w/v, or from about 2.5% to about 20% w/v of the total composition.
    [0108] In certain embodiments, a polyol solvent is added to the composition. The polyol solvent comprises a polyol or polyhydric alcohol selected from the group consisting of polyhydric alkanes (such as propylene glycol, glycerin, butylene glycol, hexylene glycol, 1,3-propanediol); polyhydric alkane esters (dipropylene glycol, ethoxydiglycol); polyalkene glycols (such as polyethylene glycol, polypropylene glycol) and mixtures thereof. In certain embodiments, the polyol solvent may be present in an amount of from 0% to 40% w/v, or from 0.5% to 20% w/v, or from 1.0% to 10% w/v of the composition.
    [0110] In certain embodiments, the compositions of the present invention have a pH of about 11 or less. In some embodiments, the compositions have a pH of from about 3 to about 7, or from about 3.5 to about 6.5, or from about 3.5 to about 5.0.
    [0112] As those skilled in the art will recognize, the pH of the composition can be adjusted or maintained using a buffer in an amount effective to provide the composition with a pH equal to or less than 11. The composition can optionally comprise at least one pH modifying agent. among the useful Included herein are acidifying agents to lower the pH, basifying agents to raise the pH, and buffering agents to maintain the pH within a desired range. For example, one or more compounds selected from acidifying, basifying, and buffering agents may be included to provide a pH of from about 2 to about 7, or in various embodiments from about 3 to about 6, or from about 4 to about 5. Any pH may be used. orally acceptable pH modifying agent including, without limitation, hydrochloric, carboxylic, and sulfonic acids, salts of acids (eg, monosodium citrate, disodium citrate, monosodium malate, etc.), alkali metal hydroxides such as sodium hydroxide, borates, silicates, imidazole and mixtures thereof. One or more pH-modifying agents are optionally present in a total amount effective to maintain the composition in an orally acceptable pH range. In certain embodiments, inorganic acids can be used as a buffer added to the composition.
    [0113] In certain embodiments, organic acids can be used as a buffer added to the composition. Organic acids suitable for use in the compositions of the present invention include, but are not limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid, and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenolsulfonic acid, and mixtures thereof, optionally, the organic acid is selected from the group consisting of benzoic acid, sorbic acid, citric acid, and mixtures thereof, or optionally, the organic acid is benzoic acid.
    [0114] Generally, the amount of buffering compound is from about 0.001% to about 20.0% of the composition. In certain embodiments, the organic acid buffer is present in amounts from about 0.001% to about 10% w/v of the composition, or from about 0.01% to about 1% of the composition.
    [0115] In certain embodiments, additional conventional components may be added as in prior art mouthwashes and mouthrinses. Although some alcohol-containing mouthwashes have a pH of about 7.0, lowering the alcohol level may require the addition of acidic preservatives, such as sorbic acid or benzoic acid, which lower pH levels. Buffer systems are then necessary to control the pH of the composition to optimal levels. This is usually achieved by the addition of a weak acid and its salt or a weak base and its salt. In some embodiments, useful systems have been found to be sodium benzoate and benzoic acid in amounts from 0.01% (or about 0.01% w/v) to 1.0% w/v (or about 1.0% w/v) of the composition, and sodium citrate and citric acid in amounts ranging from 0.001% (or about 0.001% w/v) to 1.0% w/v (or about 1.0 % w/v) of the composition, phosphoric acid and sodium/potassium phosphate in quantities of 0.01% (or about 0.01%) to 1.0% (or about 1.0%) by weight of the composition. In certain embodiments, the buffers are incorporated in amounts that maintain the pH at levels of 3.0 (or about 3.0) to 8.0 (or about 8.0), optionally 3.5 (or about 3.5) to 6.5 (or about 6.5), optionally 3.5 (or about 6.5). .5 (or about 3.5) to 5.0 (or about 5.0).
    [0116] Additional buffering agents include alkali metal hydroxides, ammonium hydroxide, organic ammonium compounds, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazole, and mixtures thereof. Specific buffering agents include monosodium phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, alkali metal carbonate salts, sodium carbonate, imidazole, pyrophosphate salts, sodium gluconate, sodium lactate, citric acid, and sodium citrate. .
    [0117] Sweeteners such as aspartame, sodium saccharin (saccharin), sucralose, stevia, acesulfame K, and the like may be added for flavor enhancement in amounts from about 0.0001% w/v to about 1.0% w/v. In certain preferred embodiments, the sweetener comprises sucralose.
    [0118] In certain embodiments, the composition further comprises flavors or flavorings to modify or magnify the flavor of the composition, or reduce or mask the sharp "stinging" or "burning" of ingredients such as thymol. Suitable flavorings include, but are not limited to, flavoring oils such as anise oil, anethole, benzyl alcohol, spearmint oil, citrus oils, vanillin, and the like may be incorporated. Other flavors such as citrus oils, vanillin, and the like can be incorporated to provide additional flavor variations. In these embodiments, the amount of flavoring oil added to the composition can be from about 0.001% to about 5% w/v, or from about 0.01% to about 0.3% w/v of the composition. total. The particular flavors or flavorings, and other flavor-enhancing ingredients, employed will vary depending on the particular flavor and sensation desired. Those of skill in the art can select and customize these types of ingredients to provide desired results.
    [0119] In certain embodiments, acceptable food colors may be used to provide a pleasing color to the compositions of the invention. These can be selected from, but are not limited to, the long list of acceptable food colors. Suitable dyes for this purpose include FD&C Yellow No. 5, FD&C Yellow No. 10, FD&C Blue No. 1, and FD&C Green No. 3. These are added in conventional amounts, typically in individual amounts of about 0.00001% wt. /v to approximately 0.0008% w/v, or from about 0.000035% w/v to about 0.0005% w/v of the composition.
    [0121] Other conventional ingredients may be used in the liquid or mouthwash compositions of this invention, including those known and used in the art. Examples of such ingredients include thickeners, suspending agents, and softeners. Useful thickeners and suspending agents in the compositions of the present invention can be found in US Patent No. 5,328,682 to Pullen et al. In certain embodiments, these are incorporated in amounts from about 0.1% w/v to about 0.6% w/v, or about 0.5% w/v of the composition.
    [0123] In some embodiments, antimicrobial preservatives may be added to the composition. Some antimicrobial preservatives that may be used include, but are not limited to, cationic antibacterials, such as sodium benzoate, polycationic polyquaternium polymers (i.e., polyquaternium-42: poly[oxyethylene(dimethylimino)ethylene(dimethylimino)ethylene] dichloride), quaternary ammonium salts or quaternary ammonium compounds, parabens (i.e., parahydroxybenzoates or esters of parahydroxybenzoic acid), hydroxyacetophenone, 1,2-hexanediol, caprylyl glycol, chlorhexidine, alexidine, hexetidine, benzalkonium chloride, domiphene bromide, cetylpyridinium (CPP), tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC), octenidine, bisbiguanides, ionic zinc or stannous agents, grapefruit extract, and mixtures thereof. Other antibacterial and antimicrobial agents include, but are not limited to: 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to as triclosan; 8-hydroxyquinoline and its salts, copper II compounds, including but not limited to, copper (II) chloride, copper (II) sulfate, copper (II) acetate, copper (II) fluoride, and copper (II) hydroxide II); phthalic acid and its salts including, but not limited to, those disclosed in US Patent No. 4,994,262, including monopotassium magnesium phthalate; bloodroot; salicylanilide; iodine; sulfonamides; phenolics; delmopinol, octapinol and other piperidino derivatives; niacin preparations; nystatin; apple extract; thyme oil; thymol; antibiotics such as augmentin, amoxicillin, tetracycline, doxycycline, minocycline, metronidazole, neomycin, kanamycin, cetylpyridinium chloride, and clindamycin; analogs and salts of the above; methyl salicylate; hydrogen peroxide; chlorite metal salts; pyrrolidone ethyl cocoyl arginate; lauroyl ethyl arginate monohydrochloride; and mixtures of all of the above. In another embodiment, the composition comprises antimicrobial phenolic compounds and mixtures thereof. Antimicrobial components may be present from about 0.001% to about 20% by weight of the oral care composition. In another embodiment, antimicrobial agents generally comprise from about 0.1% to about 5% by weight of the oral care compositions of the present invention.
    [0125] Other antibacterial agents can be basic amino acids and salts. Other embodiments may comprise arginine.
    [0127] In certain embodiments, the compositions may include bleaching agents, oxidizing agents, anti-inflammatories, chelating agents, abrasives, combinations thereof, and the like.
    [0129] A bleaching agent may be included as an active in the present compositions. Suitable bleaching actives are selected from the group consisting of alkali metal and alkaline earth metal peroxides, metal chlorites, polyphosphates, perborates including mono and tetrahydrates, perphosphates, percarbonates, peroxyacids and persulfates such as ammonium, potassium, sodium and lithium persulfates and combinations of them. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, carbamide peroxide, magnesium peroxide, zinc peroxide, strontium peroxide, and mixtures thereof. In one embodiment, the peroxide compound is carbamide peroxide. Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite. Additional bleaching actives may be hypochlorite and chlorine dioxide. In one embodiment, the chlorite is sodium chlorite. In another embodiment, the percarbonate is sodium percarbonate. In one embodiment, the persulfates are oxones. The level of these substances depends on the available oxygen or chlorine, respectively, that the molecule is capable of providing to whiten the stain. In one embodiment, the bleaching agents may be present at levels from about 0.01% to about 40%, in another embodiment from about 0.1% to about 20%, in another embodiment from about 0.5%. % to about 10%, and in another embodiment from about 4% to about 7%, by weight of the oral care composition.
    [0131] The compositions of the invention may contain an oxidizing agent, such as a source of peroxide. A peroxide source may comprise hydrogen peroxide, calcium peroxide, carbamide peroxide, or mixtures thereof. In some embodiments, the peroxide source is hydrogen peroxide. Other active peroxides may include those that produce hydrogen peroxide when mixed with water such as percarbonates, for example sodium percarbonates. In certain embodiments, the peroxide source may be in the same phase as a source of stannous ions. In some embodiments, the composition comprises from about 0.01% to about 20% of a peroxide source, in other embodiments from about 0.1% to about 5%, in certain embodiments from about 0.2 % to about 3% and in another embodiment from about 0.3% to about 2.0% of a peroxide source, by weight of the oral composition. The peroxide source can be provided as free ions, salts, complexed or encapsulated. It is desirable that the peroxide in the composition be stable. Peroxide may provide a reduction in staining, as measured by the cyclic staining test or other relevant methods.
    [0133] Anti-inflammatory agents may also be present in the compositions of the present invention. Such agents may include, but are not limited to, nonsteroidal anti-inflammatory agents (NSAIDs), oxicams, salicylates, propionic acids, acetic acids, and fenamates. Such NSAIDs include, but are not limited to, ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, ketoprofen, fenoprofen, piroxicam, nabumetone, aspirin, diflunisal, meclofenamate, mefenamic acid, oxyphenbutazone, phenylbutazone and acetaminophen. The use of NSAIDs such as ketorolac is claimed in US Patent No. 5,626,838. It discloses methods for preventing and/or treating primary and recurrent squamous cell carcinoma of the oral cavity or oropharynx by topical administration to the oral cavity or oropharynx of an effective amount of an NSAID. Suitable steroidal anti-inflammatory agents include corticosteroids, such as fluccinolone and hydrocortisone.
    [0135] The present compositions may optionally contain chelating agents, also called chelators or sequestrants, many of which also have anticalculus activity or dental substantive activity. The use of chelating agents in oral care products is advantageous because of their ability to form complexes with calcium such as that found in the cell walls of bacteria. Chelating agents can also disrupt plaque by removing calcium from the calcium bridges that help keep this biomass intact. Chelating agents also have the ability to form complexes with metal ions and thus help prevent their adverse effects on product stability or appearance. The chelation of ions, such as iron or copper, helps delay oxidative deterioration of finished products. Furthermore, chelators can, in principle, remove stains by adhering to tooth surfaces, thereby displacing color bodies or chromogens. Retention of these chelators may also prevent stain buildup due to disruption of color body binding sites on tooth surfaces. Therefore, chelators can help mitigate stains and improve cleaning. A chelator can help improve cleaning, since the fused silica and abrasives clean in a mechanical mechanism, while the chelator can help provide a chemical clean. As fused silica is a good mechanical cleaner, more stains can be removed such that a chelator may be desired to hold, suspend or complex with the stain so that it cannot re-stain the tooth surface. Additionally, the chelator can coat the tooth surface to help prevent re-staining. It may be desired to add chelators to formulations containing cationic antibacterial agents. It may be desired to add chelators to stannous-containing formulations. The chelator can help stabilize the stannous and keep a higher amount of stannous bioavailable. The chelator can be used in stannous formulations having a pH above about 4.0. In some formulations, stannous may be stable without the need for a chelator since stannous is more stable with fused silica compared to precipitated silica.
    [0137] Suitable chelating agents include soluble phosphate compounds, such as phytates and linear polyphosphates having two or more phosphate groups, including tripolyphosphate, tetrapolyphosphate, and hexametaphosphate, among others. Preferred polyphosphates are those having an average number of n phosphate groups from about 6 to about 21, such as those known commercially as Sodaphos (n=6), Hexaphos (n»13), and Glass H ( ±21). Other polyphosphorylated compounds may be used in addition to or instead of the polyphosphate, in particular polyphosphorylated inositol compounds such as phytic acid, myo-inositol pentakis (dihydrogen phosphate); myo-inositol tetrakis (dihydrogen phosphate), myo-inositol trikis (dihydrogen phosphate) and an alkali, alkaline earth metal or ammonium salt thereof. Preferred herein is phytic acid, also known as 1,2,3,4,5,6-hexakis(dihydrogenphosphate) myo-inositol or inositol hexaphosphoric acid and its alkali, alkaline earth or ammonium salts. As used herein, the term "phytate" includes phytic acid and its salts as well as the other polyphosphorylated inositol compounds. The amount of chelating agent in the compositions will depend on the chelating agent used and will typically be from at least about 0.1% to about 20%, preferably from about 0.5% to about 10%, and more preferably from about 0.5%. 1.0% to about 7%.
    [0139] Still other phosphate compounds that are useful herein for their ability to bind, solubilize and transport calcium are the above-described surface active organophosphate compounds useful as tooth substantive agents including mono, di or triesters of organic phosphate.
    [0141] Other suitable agents with chelating properties for use in plaque, calculus and stain control include polyphosphonates described in Widder et al. US Patent No. 3,678,154, US Patent 5,338,537 to White, Jr. and US Patent 5,451,401 to Zerby et al.; carbonyl diphosphonates in US Patent No. 3,737,533 to Francis; acrylic acid polymer or copolymer in US Patent No. 4,847,070, Jul. 11, 1989 to Pyrz et al. and in US Patent No. 4,661,341, April 28, 1987 to Benedict et al.; sodium alginate in US Patent No. 4,775,525, issued October 4, 1988 to Pera; polyvinylpyrrolidone in GB 741,315, WO 99/12517, and US Patent No. 5,538,714 to Pink et al.; and copolymers of vinylpyrrolidone with carboxylates in US Patent No. 5,670,138 to Venema et al. and in Lion JP Publication No. 2000-063250 Corporation.
    [0143] Still other chelating agents suitable for use in the present invention are the anionic polymeric polycarboxylates. Such materials are well known in the art, and are employed in the form of their free acids or partially or preferably fully neutralized water-soluble alkali metal (eg potassium and preferably sodium) or ammonium salts. Examples are 1:4 to 4:1 copolymers of maleic acid or anhydride with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (M.W.) of from about 30,000 to about 1,000,000. These copolymers are available, for example, as Gantrez® AN 139 (M.W. 500,000), AN 119 (M.W. 250,000), and S-97 Pharmaceutical Grade (M.W. 70,000), from GAF Chemicals Corporation. Other operative polymeric polycarboxylates include the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene, the latter available for example as Monsanto EMA No. 1103, M.W. 10,000 and EMA Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether, or N-vinyl-2-pyrrolidone. Additional operative polymeric polycarboxylates are disclosed in US Patent No. 4,138,477, February 6, 1979 to Gaffar and US Patent No. 4,183,914, January 15, 1980 to Gaffar et al. and include copolymers of maleic anhydride with styrene, isobutylene, or ethyl vinyl ether; polyacrylic, polyitaconic and polymaleic acids; and sulfoacrylic oligomers from M.W. as low as 1,000 available as Uniroyal ND-2. Other suitable chelators include polycarboxylic acids and salts thereof described in US Patent Nos. 5,015,467 to Smitherman, 5,849,271 and 5,622,689, both to Lukacovic; such as tartaric acid, citric acid, gluconic acid, malic acid; succinic acid, disuccinic acid and salts thereof, such as sodium or potassium gluconate and citrate; citric acid/alkali metal citrate combination; disodium tartrate; dipotassium tartrate; sodium and potassium tartrate; sodium hydrogen tartrate; potassium hydrogen tartrate; acid or salt form of sodium tartrate monosuccinate, potassium tartrate disuccinate and mixtures thereof. In some embodiments, there may be mixtures or combinations of chelating agents.
    [0145] Abrasives suitable for use in the present invention may include, but are not limited to: perlite, silica such as sand or quartz, ground glass, silicon carbide, ilmenite (FeTiO 3 ), zirconium oxide, zirconium silicate, topaz, TiO 2 , Precipitated Lime, Chalk, Pumice Flour, Zeolites, Talc, Kaolin, Diatomaceous Earth, Aluminum Oxide, Silicates, Zinc Orthophosphate, Sodium Bicarbonate (Baking Soda), Plastic Particles, Alumina, Hydrated Alumina , calcium carbonate, calcium pyrophosphate and mixtures thereof. The silica abrasive can be a naturally occurring amorphous silica including diatomaceous earth; or a synthetic amorphous silica such as precipitated silica; or a silica gel, such as silica xerogel; or mixtures thereof.
    [0147] Generally, an amount of abrasive suitable for use in the composition of the invention to provide an acceptable level of cleaning and polishing will be determined empirically, in accordance with techniques well known in the art. In one embodiment, a composition of the present invention includes an abrasive. In one embodiment, a composition includes a silica abrasive. In one embodiment, a silica abrasive is present in an amount of from 0.001 wt% to 30 wt%. In one embodiment, a silica abrasive is present in an amount of from 1 wt% to 15 wt%. In one embodiment, a silica abrasive is present in an amount of from 4 wt% to 10 wt%.
    [0149] Other useful oral care active and/or inactive ingredients and other examples thereof can be found in US Patent No. 6,682,722 to Majeti et al. and 6,121,315 to Nair et al.
    [0151] The compositions of the present invention can be made according to any of a variety of methods disclosed herein and known in the art. In general, the disclosed compositions can be prepared by combining the desired components in a suitable container and mixing at ambient conditions in any conventional mixing means well known in the art, such as a mechanically agitated propeller, paddle and the like.
    [0153] The compositions of the present invention can be used in a variety of methods to treat the mammalian body, in particular to disrupt a biofilm on a surface of the oral cavity. Certain methods comprise disrupting biofilm on a surface by contacting the surface comprising the biofilm with a composition of the present invention. Certain methods comprise removing biofilm from a surface by contacting the surface comprising the biofilm with a composition of the present invention. Certain methods comprise reducing bacterial attachment to a surface by contacting the surface with a composition of the present invention.
    [0155] Any suitable surface of the oral cavity may be contacted in accordance with the methods including one or more surfaces selected from the group consisting of surfaces of one or more teeth, surfaces of gums, combinations of two or more thereof, and the like. .
    [0157] In each of the above methods, the method composition can be introduced to the contacting surface by any of a variety of methods. In certain embodiments, the composition is introduced into the oral cavity and applied to the surface by the user as a mouth wash or mouth rinse. in certain In embodiments, the composition is introduced into the oral cavity and applied to the surface as a toothpaste on a tooth-cleaning article, eg, a toothbrush. The compositions of the present invention may additionally be placed in the mouth and applied to the surface as a chewing gum, lozenge, dissolvable strip, or the like.
    [0159] Furthermore, the contacting step of the methods may comprise contacting the surface with the composition for any suitable period of time. In certain embodiments, the contacting step comprises contacting the surface for less than thirty seconds. In certain embodiments, the step of contacting comprises contacting the surface with the composition for thirty seconds or more, for example, for about thirty seconds, for about 40 seconds, for about one minute, or for more than one minute.
    [0161] EXAMPLES
    [0163] Formulations outside the scope of the claims are provided as reference formulations only.
    [0165] Example 1: Biofilm Prevention Performance of Compounds
    [0167] Formulations A1-J1 as shown in Table 1 were made by dissolving one of nine compounds: transcis-aconitic acid, succinic acid, adenosine, quinic acid, inosine, shikimic acid, uridine, oxalic acid, or epicatechin, in an aqueous solution containing it contained ethanol and a benzoic acid buffer. Each of the nine formulations was tested in a biofilm prevention assay as described below.
    [0169] The formulations were used to treat film coated hydroxyapatite pin caps by immersing the caps in the formulations as treatment solutions. The peg caps were then removed from the treatment solutions and inoculated overnight with human whole saliva, to generate a mixed-species saliva-derived biofilm. The amount of biofilm developed on each peg cap was quantified by measuring ATP using a bioluminescence reaction and compared to the amount of biofilm developed on a peg cap exposed to the negative control of benzoic acid/ethanol solution (Sample J). Results are reported as log RLU, with a lower value corresponding to less biofilm. The resulting log RLUs are reported in Table 1.
    [0171] T l 1: F rm l i n n v m n n
    [0173]
    [0176] Example 2: Exploration of different ratios and concentration ranges for succinic acid/trans-aconitic acid
    [0177] Succinic acid and trans-aconitic acid were formulated into complete mouthwash formulations and their concentrations and proportions were systematically varied. The amounts and materials of each formulation are shown in Tables 2 through 5. Formulations containing succinic acid, trans-aconitic acid, and mixtures of both succinic acid and trans-aconitic acid were made. The total concentration of succinic acid plus trans-aconitic acid used in the formulations shown in Tables 3 to 6 is 10.5 mM, 21 mM, 42 mM and 63 mM, that is, between 0.12% w/w and the 1.1% w/w, respectively. These formulations were prepared by dissolving water-soluble components, including succinic acid, trans-aconitic acid, Poloxamer 407, sodium lauryl sulfate, sodium benzoate, saccharin, sucralose, sorbitol, and FD&C Green No. 3, in water. Separately, all non-water soluble components including menthol, thymol, eucalyptol, methyl salicylate, flavor and benzoic acid were dissolved in propylene glycol. The propylene glycol solution was then added to the aqueous solution and mixed.
    [0178]
    [0179]
    [0180]
    [0181]
    [0182]
    [0183] Two methods were used to test the efficacy of the formulations. The first was a "Pretreatment Multi-Treatment Static Biofilm Test Method", while the second was a "Prevention Test Method". The test methods are described below.
    [0184] Multi-treatment static biofilm test method with pretreatment
    [0185] The formulations were prepared as described above using conventional mixing technology. The pH of the formulations were all approximately pH 4.2. A plate of polystyrene pegs (96 pegs, N=8 per group) was exposed to saliva for thirty minutes to form a film on each peg at a temperature of 35°C. Then, for each formulation, eight pegs ( N=8) for ten minutes with the formulation using an orbital shaker set at 500 RPM at room temperature. As a negative control, eight pegs (N=8) were pretreated for ten minutes with sterile water. A salivary biofilm was then grown 24 hours on these polystyrene peg plates at a temperature of 35°C. The pegs were re-treated (N=8) for thirty seconds with the same formulation used for pre-treatment using an orbital shaker. set to 500 RPM at room temperature. Retreatments were applied twice daily for two days, a total of six treatments included the pretreatment.
    [0186] Once all treatments were complete, the biofilm on each peg was neutralized and rinsed. Biofilm was collected by sonication using a Q-Sonica Q700 ultrasonic liquid processor with 431MP4-00 microplate horn damper and 0.5:1 inverse gain amplifier (Q-Sonica, Newtown, Connecticut). Using a Celsis Rapid Detection RapiScreen kit (Celsis International PLC, Chicago, IL), bacteria were lysed with Celsis Luminex and then adenosine triphosphate (ATP) of the lysed bacteria was measured using the Celcis Luminate bioluminescence marker and a Celsis Luminometer. Centro LB 960 microplates supplied by Berthold Technologies (Wildbad, Germany). Data was reported in log RLUs (relative light units) where decreasing log RLUs indicated that fewer viable bacteria remained on the biofilm substrate.
    [0187] Prevention test method
    [0188] The formulations were prepared as described above using conventional mixing technology. The pH of the formulations were all about pH 4.2. A plate of hydroxyapatite-coated polystyrene pegs (96 pegs, N=8 per group) was exposed to saliva for one minute to form a film at a temperature of 35°C. Then, for each formulation, eight pegs ( N=8) for ten minutes with the formulation using an orbital shaker set at 500 RPM at room temperature. As a negative control, eight pegs (N=8) were pretreated for ten minutes with sterile water. Then, a salivary biofilm was cultured for 16 hours on these polystyrene pin plates at a temperature of 35°C.
    [0189] Once all treatments were complete, the biofilm on each peg was neutralized and rinsed. Biofilm was collected by sonication using a Q-Sonica Q700 ultrasonic liquid processor with 431MP4-00 microplate horn damper and 0.5:1 inverse gain amplifier (Q-Sonica, Newtown, Connecticut). Using a Celsis Rapid Detection RapiScreen kit (Celsis International PLC, Chicago, IL), bacteria were lysed with Celsis Luminex and then adenosine triphosphate (ATP) of the lysed bacteria was measured using the Celcis Luminate bioluminescence marker and a Celsis Luminometer. Centro LB 960 microplates supplied by Berthold Technologies (Wildbad, Germany). Data was reported in log RLUs (relative light units) where decreasing log RLUs indicated that fewer viable bacteria remained on the biofilm substrate.
    [0190] The results of the "Pretreatment Multi-Treatment Static Biofilm Test Method" and the "Prevention Test Method" for each of the formulations are summarized in Table 6.
    [0191] Figures 1 and 2 are graphs of percent biofilm removal after multiple treatments (vs. water) vs. percent reduction in bacterial attachment (vs. water) for formulations A21-L21 containing succinic acid (SA) and trans-aconitic acid (tAA) shown in Table 3 above. The dotted lines in the figures are the expected results in a straight line for the mixtures of SA and tAA. The figures show that when succinic acid and trans-aconitic acid are combined in ratios between 0.9:1 and 14.1:1 (succinic acid:trans-aconitic acid), the results surprisingly deviate from the expected results.
    [0192] Table 6 shows the same surprising results when the distance from the expected results for mixtures of succinic acid and trans-aconitic acid is examined for other concentrations of the combined acid materials in the Table.
    [0193] Table 6: Summary results of multi-treatment prevention tests for formulations containing succinic acid (SA) and trans-aconitic acid (tAA).
    [0194] reduction
    [0195]
    [0196] bacterial reduced
    [0197] wí% [SA]/[tAA] (% reduced bacterial multil'locRLUl biofilm binding (% (treatment prevention)** over multi- acid compared to llogRLU control) reduced
    [0198] over treatment)* with water control) control compared to water water) with control
    [0199] of water
    [0200] 110.5 0.18 0: S 4.66 35.72 6.00 6.40 42.12 42.12 A 10.5 0.15 0.9:1 4.53 37.52 5.86 S 58 43.11 46.1 O
    [0201] c B10.5 0.14 1.7:1 4.42 39.03 5.79 9.67 43.44 48.7 i
    [0202] i CIO.5 0.14 4.2:1 4.46 38.48 5.61 12.48 43.82 50.96 & w
    [0203] H i 0.5 0.12 1: 0 5.13 29.24 5.45 14.98 44.22 44.22 0.00 water - 7.25 0.00 0.00 0.00 110.5 0.00 O.41 0.18 0: 1 5.13 29.92 5.81 9.36 39.28 39.28 0.13 DS0.5 5.5: 1 4.48 38.80 5.63 12.17 41.75 50.97
    [0204] g
    [0206] <5
    [0207] t & í 010.5 03.27 0.12: 5.44 25.68 5.48 14.51 1 42 40.19 1110.5 J4 0.12 1: 0 5.37 26.64 5.41 15.60 42.24 42.24 0.00 water - 0.00 6.41 0.00 0.00 7.32 0 0.37 0 L21: 1 4.61 39.10 5.67 14.22 53.32 53.32 A21 0.35 0.1: 1 4.6 39.23 5.65 14.52 53.32 53.75 B21 0.33 0.3: 1 4.92 35.01 5.58 1558 53.32 50.59 at C21 0.32 0.5: 1 4.81 36.46 5.5 16.79 53.31 53.25 D21 0.30 0.9: 1 4.43. 41.61 5.29 19.97 58
    [0208] I heard
    [0209] T & I E2 1.8 i 0.28: 1 4.14 45.31 5.26 20.42 53.31 65.73 0.26 F2l 4.0: 1 4.65 38.57 5.2 2133 53.30 59.9 0.25 K21 1: 0 5.23 30.91 5.13 22.39 53.30 53.3 Water 0.00 - 7.57 0.00 6.61 0.00 0.00 0 reduction
    [0210] to Reduction , Elimination Additive Reduction
    [0211] Actual Planned Elimination of
    [0212] of Reduction in % of total biofilm film film of
    [0213] tAA] (% bacterial attachment reduction of (prevention Formula SA+iAA biofilm mullí- wt% ISAM
    [0214] Bacterial OogRLU) reduced (% (prevention treatment)** over reduced multi- compared control (logRLU) over treatment)* with water control) control compared with water control) with control
    [0215] of water
    [0216] L21 0.37 0:1 5.1 30.33 5.82 7.77 38.10 38.1 G21 0.26 5.6:1 4.29 41.39 5.48 13.15 41.31 54.54 H21 0.26 8.8:1 4.6 35.93 5 47 13.31 41.49 49.24 1
    [0217] B 121 0. 6 14.1: 1 5.05 31.01 5.44 13.79 41.63 44.8 & Í J21 0.25 27.6: 1 5.29 27.73 5.43 13.95 41.75 41.68 K21 0.25 1: 0 5 31 27.46 5.4 J 4.42 41.88 41.88 Water 0.00 - 7.32 0.00 6.31 0.00 0.00 0 142 073 0;J 4.77 34.21 5.82 9.20 43.4! 43.41 A42 N ^ 9 09: 1 4.51 37.79 5.73 10.61 47.53 48.4 B42 0.56 1.7: 1 4.34 40.14 51.84 € 48.88 4.2: 1 4.41 39.17 5.41 15.60 50,43 54.77 H42 0.50 1: 0 4.6o 35.72 5.36 16.38 52.10 52.1 water 0.00 — 7.25 0.00 6.41 0.00 0.00 0 142 0.73 0:1 5.05 31.01 5.73 10.61 41.62 41.62
    [0218] E42 0.51 8 8:1 4.53 38.11 5.4! 15.60 46.50 53.71
    [0219] water 0.00 ... 7.32 0.00 6.41 0.00 0.00 0 !63 110 0:1 5.48 25.85 5.86 12.14 37.99 37.99
    [0220] E63 0.77 8.8: 1 4,62 37.48 5.5 17.54 44.04 55.02 F63 0.76 13.7: 1 5.24 29.09 5,41 18.89 44 R7 47.98 G63 0.76 28.1: 1 521 30.85 5.39 19.19 37.99 50.04 H63 0.74 1: 0 5.58 24.49 5,32 20.24 44.73 44.73 Water 0.00 7.39 0.00 6.67 000 0.00 0
    [0222] Example 3: Biofilm Prevention Performance of Compounds
    [0223] Formulations A2-J2 as shown in Table 7 were made and tested in the biofilm prevention assay. The formulations were tested in an in vitro static multi-treatment mixed species biofilm assay. Film-coated pin caps were pretreated with each formulation prior to biofilm growth. The treated peg caps were then inoculated with whole human saliva for 24 hours to develop a mixed-species saliva-derived biofilm. This biofilm was treated with each formulation twice daily over the course of 60 hours, for a total of five 30-second treatments. Results are reported as log RLU and are shown in Table 7, with a lower value corresponding to less biofilm. The results were then used to create contour surfaces to maximize activity with varying concentrations of succinic acid and trans-aconitic acid. A positive control (Sample J2) composed of a mouthwash containing standard essential oil was also formulated and tested.
    权利要求:
    Claims (12)
    [1]
    1. A composition comprising succinic acid, aconitic acid and a carrier, said succinic acid and aconitic acid being present in the composition in a ratio of succinic acid to aconitic acid of from 0.9:1 to 14:1 by weight and wherein the total combined amount of succinic acid and aconitic acid is 0.1 to 2% w/w of the composition.
    [2]
    2. The composition of claim 1 having a ratio of succinic acid to aconitic acid of from 0.9:1 to 9:1; or having a ratio of succinic acid to aconitic acid of from 0.9:1 to 6:1.
    [3]
    3. The composition of any preceding claim having succinic acid and aconitic acid in a total combined amount of 0.1 to 1% w/w of the composition; or
    having succinic acid and aconitic acid in a total combined amount of 0.1 to 0.5% w/w of the composition; or having succinic acid and aconitic acid in a total combined amount of 0.1 to 0.3% w/w of the composition.
    [4]
    4. The composition of claim 1 wherein said carrier comprises water;
    optionally, wherein said carrier comprises a water/alcohol mixture.
    [5]
    5. The composition of claim 4 wherein said carrier comprises a water/alcohol mixture and wherein said composition comprises alcohol in an amount of 10% v/v or less by volume of the total composition.
    [6]
    6. The composition of any of claims 1 to 3 wherein said composition is free of alcohol.
    [7]
    7. The composition of any preceding claim wherein said aconitic acid is frans-aconitic acid.
    [8]
    8. The composition of any preceding claim wherein said composition is an oral care composition further comprising at least one surfactant selected from the group consisting of anionic, nonionic, cationic, amphoteric, zwitterionic, and combinations of two or more of the same.
    [9]
    9. The oral care composition of any preceding claim further comprising at least one essential oil selected from the group consisting of thymol, eucalyptol, menthol, methyl salicylate, isomers of each of these compounds, and combinations of two or more of the same.
    [10]
    10. The oral care composition of any preceding claim, wherein said composition is in the form of a mouth wash, mouth rinse, toothpaste, chewing gum, lozenge, or dissolvable strip.
    [11]
    11. The oral care composition of claim 10 wherein said composition is in the form of a mouth wash or mouth rinse.
    [12]
    12. The oral care composition of claim 10 wherein said composition comprises succinic acid and frans-aconitic acid in a total combined amount of 0.1 to 1% w/w of the composition.
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    同族专利:
    公开号 | 公开日
    ES2860981T3|2021-10-05|
    EP3261608B9|2021-10-27|
    RU2017133244A|2019-03-28|
    EP3261608A1|2018-01-03|
    AU2016222687A1|2017-08-24|
    CA2977351A1|2016-09-01|
    WO2016138211A1|2016-09-01|
    RU2734759C2|2020-10-23|
    BR112017018187A2|2018-04-17|
    BR112017018187B1|2021-06-01|
    CN107257678A|2017-10-17|
    EP3261608B1|2021-02-17|
    US9326924B1|2016-05-03|
    AU2021201962A1|2021-04-29|
    DK3261608T5|2021-12-13|
    JP2018506567A|2018-03-08|
    DK3261608T3|2021-03-22|
    JP6821581B2|2021-01-27|
    RU2017133244A3|2019-04-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE519897A|1952-05-13|
    US3678154A|1968-07-01|1972-07-18|Procter & Gamble|Oral compositions for calculus retardation|
    US3737533A|1971-04-28|1973-06-05|Upjohn Co|Compositions and methods of combatting insects using 1'-variable-1',1'-dihalohalobenzeneazomethanes|
    US4051234A|1975-06-06|1977-09-27|The Procter & Gamble Company|Oral compositions for plaque, caries, and calculus retardation with reduced staining tendencies|
    US4138477A|1976-05-28|1979-02-06|Colgate Palmolive Company|Composition to control mouth odor|
    US4183914A|1977-12-19|1980-01-15|Abdul Gaffar|Magnesium polycarboxylate complexes and anticalculus agents|
    US4661341A|1984-10-30|1987-04-28|The Procter & Gamble Company|Oral compositions|
    US4775525A|1985-12-16|1988-10-04|Ivo Pera|Oral hygiene formulation containing sodium alginate|
    US4847070A|1987-10-08|1989-07-11|The Procter & Gamble Company|Anticalculus compositions|
    US4994262A|1988-10-14|1991-02-19|The Procter & Gamble Company|Oral compositions|
    US5190747A|1989-11-06|1993-03-02|Lion Corporation|Oral or detergent composition comprising a nonionic surface active agent|
    US5015467A|1990-06-26|1991-05-14|The Procter & Gamble Company|Combined anticalculus and antiplaque compositions|
    AT120951T|1990-10-25|1995-04-15|Boots Co Plc|Mouthwash.|
    GB9204414D0|1992-02-29|1992-04-15|Smithkline Beecham Plc|Method of treatment|
    US5451401A|1993-09-29|1995-09-19|The Procter & Gamble Company|Diphosphonic acid esters as tartar control agents|
    US5338537A|1993-10-05|1994-08-16|The Procter & Gamble Company|Oral compositions|
    US5560905A|1994-05-13|1996-10-01|The Proctor & Gamble Company|Oral compositions|
    US5849271A|1995-06-07|1998-12-15|The Procter & Gamble Company|Oral compositions|
    EP0691124A1|1994-07-07|1996-01-10|Sara Lee/DE N.V.|Mouth care products|
    US5626838A|1995-03-13|1997-05-06|The Procter & Gamble Company|Use of ketorolac for treatment of squamous cell carcinomas of the oral cavity or oropharynx|
    JPH08289768A|1995-04-19|1996-11-05|Kiyuu & C:Kk|Antimicrobial agent for food|
    AU4428397A|1996-09-20|1998-04-14|Warner-Lambert Company|Oral compositions containing a zinc compound|
    WO1999012517A1|1997-09-09|1999-03-18|Smithkline Beecham Corporation|Tooth whitening preparations|
    US7125543B2|1998-05-04|2006-10-24|Milton Hodosh|Method and composition for preventing tooth hypersensitivity when using passive bleaching agents|
    JP2000063250A|1998-08-18|2000-02-29|Lion Corp|Composition for oral cavity|
    US6221340B1|1999-04-08|2001-04-24|Warner-Lambert Company|Zinc containing dentifrice compositions|
    US6416745B1|2001-05-03|2002-07-09|Block Drug Company, Inc.|Dental composition for treating hypersensitive teeth|
    RU2190387C1|2001-06-19|2002-10-10|Общество с ограниченной ответственностью "Лечебно-диагностическая фирма "Медик"|Preparation for mouth gargling|
    US6682722B2|2001-09-19|2004-01-27|The Procter & Gamble Company|Oral compositions providing enhanced overall cleaning|
    FR2830759B1|2001-10-15|2003-12-12|Oreal|COMPOSITION IN THE FORM OF AN OIL-IN-WATER EMULSION CONTAINING A SILICONE COPOLYMER AND ITS IN PARTICULAR COSMETIC USES|
    JP2005015369A|2003-06-25|2005-01-20|Lion Corp|Composition for oral cavity|
    US7084104B2|2003-08-28|2006-08-01|Johnson & Johnson Consumer Company Inc.|Mild and effective cleansing compositions|
    RU2235534C1|2003-10-28|2004-09-10|Киппер Светлана Николаевна|Preparation for oral rinsing|
    EP1830638A2|2004-12-09|2007-09-12|The Dial Corporation|Compositions having a high antiviral and antibacterial efficacy|
    US9629361B2|2006-02-09|2017-04-25|Gojo Industries, Inc.|Composition and method for pre-surgical skin disinfection|
    US7417020B2|2006-05-05|2008-08-26|Johnson & Johnson Consumer Companies, Inc.|Compositions comprising low-DP polymerized surfactants and methods of use thereof|
    JP5397181B2|2009-11-18|2014-01-22|ライオン株式会社|Oral spray composition and oral preparation|
    PL2336285T3|2009-12-18|2014-01-31|Procter & Gamble|Composition comprising microcapsules|
    WO2012001347A1|2010-06-29|2012-01-05|Ucl Business Plc|Products with oral health benefits|
    EP2760417B1|2011-09-30|2020-11-11|Rubicon Research Private Limited|Oral care compositions|
    AU2013408773B2|2013-12-27|2017-10-19|Colgate-Palmolive Company|Prebiotic oral care compositions containing carboxylic acids|
    US9326925B1|2015-02-26|2016-05-03|Johnson & Johnson Consumer Inc.|Compositions comprising combinations of organic acids|US9326925B1|2015-02-26|2016-05-03|Johnson & Johnson Consumer Inc.|Compositions comprising combinations of organic acids|
    MX2018013276A|2016-05-26|2019-03-28|Kimberly Clark Co|Anti-adherent compositions and methods of inhibiting the adherence of microbes to a surface.|
    US20210307324A1|2018-06-04|2021-10-07|Conopco, Inc., D/B/A Unilever|Preservation compositions|
    US11058634B2|2018-11-19|2021-07-13|Steven J. Edwards|Adherent oral pharmabiotic delivery strip|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US14/632,447|US9326924B1|2015-02-26|2015-02-26|Compositions comprising combinations of organic acids|
    PCT/US2016/019476|WO2016138211A1|2015-02-26|2016-02-25|Compositions comprising combinations of organic acids|
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